Clinical, epidemiologic, genetic, and experimental studies have demonstrated that diabetes mellitus is a heterogenous group of disorders rather than a single disease. The objective of this project is to demonstrate some of the genetic heterogeneity of diabetes at a cellular level, using cultured skin fibroblasts as a moel system. Cultures will be initiated from patients with various types of diabetes, including juvenile and maturity-onset types, the maturity-onset diabetes of the young, and mendelian diseases associated with glucose intolerance. Insulin responsiveness will be assessed by studying the hormonal stimulation of amino acid transport in serum-starved cells. The dose-response relationships for insulin enhancement of the initial rate of transport of the non-metabolized amino acid alpha-aminoisobutyric acid (AIB) will be defined, and insulin binding measured. The effects of preincubation of the cells with glucocorticoids and with oral hypoglycemic agents on their insulin responsiveness will also be studied. It is hoped that these approaches will demonstrate differences in the patterns of in vitro insulin responsiveness which reflect clinical and genetic differences observed in vivo. The validity of these cellular markers of genetic heterogeneity will be tested by examining fibroblast cultures from both affected and unaffected members of families with specific subtypes of diabetes. The delineation of such cellular markers might provide models for studying the basic defects in these syndromes, an could provide valid markers of prediabetic states for use in genetic counseling and early intervention therapy.